iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer.
iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer.
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DOI：
10.1158/1535-7163.mct-17-1090
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发表时间：
2018-11
影响因子：
5.7
通讯作者：
Bhatia SN
中科院分区：
文献类型：
--
作者：
Lo JH;Hao L;Muzumdar MD;Raghavan S;Kwon EJ;Pulver EM;Hsu F;Aguirre AJ;Wolpin BM;Fuchs CS;Hahn WC;Jacks T;Bhatia SN
胰腺癌是癌症死亡的主要原因之一，5年生存率为8.5%。在改善治疗方面缺乏重大进展反映了我们无法克服胰腺导管腺癌（PDAC）的纤维间质屏障，以及缺乏针对其遗传基础的新方法。RNA干扰有望靶向驱动PDAC的关键突变；然而，目前还不存在一种能够将PDAC作为载体并破坏基质的核酸载体。考虑到环肽iRGD通过与αvβ3/5整合素和neuropilin-1的相互作用介导肿瘤靶向和穿透，我们假设结合细胞穿透肽和iRGD的“串联”肽可以包封siRNA，形成能够将siRNA递送到PDAC的肿瘤穿透纳米复合物（TPNs）。使用直接结合的iRGD是合理的受体表达模式在人类PDAC活组织检查。在这项工作中，我们用聚乙二醇（PEG）肽偶联物优化iRGD TPNs，使其能够全身递送到疾病部位。我们在PDAC细胞系和具有免疫能力的PDAC基因工程小鼠模型中发现，TPNs可以有效地敲低siRNA靶点。此外，我们验证了它们在三维类器官和原位肿瘤中的穿透能力。在小鼠治疗试验中，传递抗kras siRNA的TPNs可显著延缓肿瘤生长。因此，iRGD TPNs不仅克服了治疗的物理障碍，而且利用基质实现了金标准遗传靶标的敲低，因此有望治疗PDAC。此外，这种输送平台的模块化结构允许方便地适应未来胰腺癌的基因候选靶点。
Pancreatic cancer is one of the leading causes of cancer death, with 5-year survival of 8.5%. The lack of significant progress in improving therapy reflects our inability to overcome the desmoplastic stromal barrier in pancreatic ductal adenocarcinoma (PDAC) as well as a paucity of new approaches targeting its genetic underpinnings. RNA interference holds promise in targeting key mutations driving PDAC; however, a nucleic acid delivery vehicle that homes to PDAC and breaches the stroma does not yet exist. Noting that the cyclic peptide iRGD mediates tumor targeting and penetration through interactions with αvβ3/5 integrins and neuropilin-1, we hypothesized that “tandem” peptides combining a cell-penetrating peptide and iRGD can encapsulate siRNA to form tumor-penetrating nanocomplexes (TPNs) capable of delivering siRNA to PDAC. The use of directly-conjugated iRGD is justified by receptor expression patterns in human PDAC biopsies. In this work, we optimize iRGD TPNs with polyethylene glycol (PEG)-peptide conjugates for systemic delivery to sites of disease. We show that TPNs effectively knockdown siRNA targets in PDAC cell lines and in an immunocompetent genetically-engineered mouse model of PDAC. Furthermore, we validate their tumor-penetrating ability in three-dimensional organoids and autochthonous tumors. In murine therapeutic trials, TPNs delivering anti-Kras siRNA significantly delay tumor growth. Thus, iRGD TPNs hold promise in treating PDAC by not only overcoming physical barriers to therapy, but by leveraging the stroma to achieve knockdown of the gold standard genetic target. Moreover, the modular construction of this delivery platform allows for facile adaptation to future genetic target candidates in pancreatic cancer.